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Abstract
Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.
Highlights
Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction
Using repeated morphine exposure, which allowed for a temporal regulation of both viral expression and opiate exposure, we showed that F/G-actin ratios were restored by herpes simplex viruses (HSVs)-drebrin (Fig. 4a), which occurred by reversing the opiateinduced decrease in F-actin pools (Supplementary Fig. 9a, b)
In agreement with our whole-cell findings demonstrating that HDAC2 regulates drebrin expression, we found that HDAC2 was upregulated in dopamine receptor 1 (D1) but not dopamine receptor 2 (D2) medium spiny neurons (MSNs) (Supplementary Fig. 13) following heroin SA
Summary
Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; the underlying transcriptional and cellular events mediating this remain unknown. We demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc. One of the most difficult challenges in the treatment of opiate addiction is the life-long propensity to relapse[1], contributing to the nearly 50,000 cases of overdose each year[2]. Actin cycling is tightly controlled by robust transcription and epigenetic regulation of genes encoding cytoskeletal proteins[21,22] One such protein is drebrin, which modulates both dendritic spine plasticity and synaptic function and is dysregulated in certain disease states[23,24]. The role of HDACs in mediating opioid-induced cellular plasticity and the therapeutic potential of HDAC inhibition in heroin abuse remain understudied
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